ADVL1522: A phase 2 study of lorvotuzumab mertansine (IMGN901) in children with relapsed or refractory wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, or synovial sarcoma—A Children's Oncology Group study

James I. Geller, Joseph G. Pressey, Malcolm A. Smith, Rachel A. Kudgus, Mariana Cajaiba, Joel M. Reid, David Hall, Donald A. Barkauskas, Stephen D. Voss, Steve Y. Cho, Stacey L. Berg, Jeffrey S. Dome, Elizabeth Fox, Brenda J. Weigel

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities. Methods: Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21-day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56-positive cell counts, and tumor CD56 expression were assessed. Results: Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non–dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response. Conclusions: Lorvotuzumab mertansine (110 mg/m2) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.

Original languageEnglish (US)
Pages (from-to)5303-5310
Number of pages8
JournalCancer
Volume126
Issue number24
DOIs
StatePublished - Dec 15 2020

Bibliographical note

Funding Information:
This study was supported by an Operations Center Grant from the National Clinical Trials Network (U10CA180886), a Statistics and Data Center Grant from the National Clinical Trials Network (U10CA180899), and the St. Baldrick's Foundation (P30 CA015083). The pharmacokinetic analyses were supported by a grant from the National Cancer Institute (P30 CA015083). The PK of lorvotuzumab mertansine, total antibody, and DM1 was characterized in 15 eligible patients. The median age was 11.4 years (range, 3.7-26.3 years); 9 were male. Concentration-time profiles for lorvotuzumab mertansine and total antibody in serum and for maytansinoid (DM1) in plasma are illustrated in Figure 1, and the PK parameters are summarized in Table 4. The peak concentration (Cmax) was achieved at a median of 1.67 hours (range, 1.22-7.05 hours) for lorvotuzumab mertansine, at a median of 3.28 hours (range, 1.18-7.58 hours) for total antibody, and at a median of 1.57 hours (range, 1.05-3.15 hours) for maytansinoid. The median values of Cmax and exposure (area under the curve [AUC]) were 0.87 ?g/mL and 26.7 h ?g/mL, 125 ?g/mL and 4183 h ?g/mL, and 156 ?g/mL and 3692 h ?g/mL for maytansinoid, total antibody, and total lorvotuzumab mertansine, respectively. PK comparative analyses did not demonstrate significant differences between female and male patients (including the total antibody AUC and maytansinoid) or between patients younger than 12 years and patients 12 years old or older for all parameters assessed. Abbreviations: AUC, area under the curve; Cmax, maximum concentration; Tmax, time to maximum concentration. Lorvotuzumab mertansine and total antibody were measured in serum; maytansinoid (DM1) was measured in plasma. IMGN901, n?=?7; total antibody, n?=?7; DM1, n?=?9. IMGN901, n?=?6; total antibody, n?=?6; DM1, n?=?6. IMGN901, n?=?8; total antibody, n?=?8; DM1, n?=?9. IMGN901, n?=?5; total antibody, n?=?5; DM1, n?=?6. Sixty-two patients were enrolled into the study; 1 patient was ineligible because of a tumor not meeting the definition of measurable disease according to RECIST. The median age of the 61 eligible patients was 13.9 years (range, 2.8-26.3 years). Twenty-six patients (43%) were female, and 35 (57%) were male. The tumor histologies of the eligible patients included Wilms tumor (n?=?17), rhabdomyosarcoma (n?=?16), neuroblastoma (n?=?12), synovial sarcoma (n?=?10), MPNST (n?=?5), and pleuropulmonary blastoma (n?=?1). Patient characteristics are listed in Table 1. One of the 61 eligible patients was unevaluable for a response assessment on account of not receiving any therapy. One patient with rhabdomyosarcoma experienced a partial response after cycle 2 followed by progression after 11 cycles. Stable disease lasting at least 6 cycles as a best response was demonstrated in 3 patients (25%) with neuroblastoma and in 3 patients (30%) with synovial sarcoma. One patient with synovial sarcoma with documented stable disease achieved a confirmed delayed complete response by cycle 8. This response persisted through all planned 17 cycles of therapy, with the patient in sustained remission 2 years after enrollment. Nine of the 61 eligible patients were unevaluable for a toxicity assessment because of rapid progression of the disease (n?=?6), death due to the underlying disease (n?=?2), or no treatment (n?=?1). Seven of the 9 patients initially enrolled were evaluable for toxicity assessment; they included 1 patient with a DLT (grade 3 hyperglycemia possibly related to lorvotuzumab mertansine). Among all patients, 22 reportable adverse events at least possibly related to lorvotuzumab mertansine were recorded; they included grade 5 colonic perforation (n?=?1) with a grade 4 colonic fistula (n?=?1), grade 3 anemia (n?=?2), increased alanine aminotransferase (n?=?3), decreased lymphocyte counts (n?=?2), grade 3 peripheral motor neuropathy (n?=?1), and grade 3 peripheral sensory neuropathy (n?=?1). Among the patients who received at least 4 cycles of therapy, 1 of 22 developed a neuropathy. No patient required any dose reduction. At the discretion of the treating physician, a single patient received approximate 50% dosing during cycles 5 and 6 of treatment; this coincided with concurrent radiotherapy. Lorvotuzumab mertansine?related toxicities are summarized in Table 2. Fifty-four tumor samples obtained before lorvotuzumab mertansine therapy were deemed sufficient for CD56 expression analysis; 3+ CD56 expression was detected in 40 tumors, and 2+ expression was detected in 6 others. Overall, the tumor CD56 expression in prechemotherapy archival tumor specimens was scored as 0 (8%), 1+ (4%), 2+ (12%), or 3+ (76%; Table 3). Abbreviation: INS, insufficient sample for testing. Paired peripheral blood samples from day 1 (before therapy) and either day 8 or 11 (after therapy) for the measurement of CD56-positive leukocyte counts were available from 12 patients. The absolute CD56 ratios comparing posttherapy and pretherapy CD56 counts ranged from 0.08 to 2.78 with a geometric mean of 0.281, and they demonstrated a significant decrease in CD56-positive leukocyte counts after treatment (71.9%; P?=.0012). In contrast, total leukocyte counts after treatment did not change significantly (P?=.278). Such data confirm an on-target CD56-directed drug effect. The PK of lorvotuzumab mertansine, total antibody, and DM1 was characterized in 15 eligible patients. The median age was 11.4 years (range, 3.7-26.3 years); 9 were male. Concentration-time profiles for lorvotuzumab mertansine and total antibody in serum and for maytansinoid (DM1) in plasma are illustrated in Figure 1, and the PK parameters are summarized in Table 4. The peak concentration (Cmax) was achieved at a median of 1.67 hours (range, 1.22-7.05 hours) for lorvotuzumab mertansine, at a median of 3.28 hours (range, 1.18-7.58 hours) for total antibody, and at a median of 1.57 hours (range, 1.05-3.15 hours) for maytansinoid. The median values of Cmax and exposure (area under the curve [AUC]) were 0.87 ?g/mL and 26.7 h ?g/mL, 125 ?g/mL and 4183 h ?g/mL, and 156 ?g/mL and 3692 h ?g/mL for maytansinoid, total antibody, and total lorvotuzumab mertansine, respectively. PK comparative analyses did not demonstrate significant differences between female and male patients (including the total antibody AUC and maytansinoid) or between patients younger than 12 years and patients 12 years old or older for all parameters assessed. Abbreviations: AUC, area under the curve; Cmax, maximum concentration; Tmax, time to maximum concentration. Lorvotuzumab mertansine and total antibody were measured in serum; maytansinoid (DM1) was measured in plasma. IMGN901, n?=?7; total antibody, n?=?7; DM1, n?=?9. IMGN901, n?=?6; total antibody, n?=?6; DM1, n?=?6. IMGN901, n?=?8; total antibody, n?=?8; DM1, n?=?9. IMGN901, n?=?5; total antibody, n?=?5; DM1, n?=?6. PK sampling was required for the first 9 patients enrolled and was optional for patients enrolled subsequently. Peripheral blood samples were collected to determine lorvotuzumab mertansine, total antibody (which measured the concentration of both free HuN901 antibody and conjugated antibody [serum]), and free DM1 (plasma). Concentrations of lorvotuzumab mertansine and total antibody were measured with validated enzyme-linked immunoabsorbent assays. Free DM1 was measured with a validated liquid chromatography?tandem mass spectrometry assay. Blood samples were drawn at the following time points on day 1: before treatment; at the end of the infusion; and 2, 6, 24, and 72 to 120 hours after the end of the infusion. They were also drawn on day 8 before treatment. PK parameters were calculated with standard noncompartmental analysis (Phoenix WinNonlin 6.4; Pharsight Corporation, Mountain View, California).18,19 Patients aged 12 months to 30 years with a diagnosis of recurrent or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, MPNST, or synovial sarcoma were eligible. The primary cohorts were defined in terms of Wilms tumor, rhabdomyosarcoma, and neuroblastoma because of the potential for benefit and the feasibility of accrual. Patients were required to have a Lansky or Karnofsky performance score ? 50 and to have fully recovered from the acute toxicities of prior therapy. Patients had adequate hematopoietic, renal, liver, and cardiac function. Patients were required to have measurable tumors according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1,17 except for neuroblastoma patients with evaluable metaiodobenzylguanidine (MIBG)-avid disease. The exclusion criteria included active central nervous system metastases, grade 2 or higher central nervous system or peripheral neuropathies, pregnancy, and active breastfeeding. Patients receiving corticosteroids must have been on a stable or decreasing dose for 7 days before trial enrollment. Patients taking agents to treat or prevent graft-versus-host disease or organ rejection after transplantation were not eligible. The trial was approved by the National Cancer Institute's central institutional review board. Written informed consent and assent were obtained in accordance with federal and institutional guidelines. The first 9 patients were enrolled at Children's Oncology Group phase 1 and pilot consortium institutions for the monitoring of adverse events. Subsequent patients could be enrolled at any Children's Oncology Group member institution in the United States. Lorvotuzumab mertansine at the recommended phase 2 dose of 110 mg/m2 was administered via intravenous infusion on days 1 and 8 of each 21-day cycle. All patients were premedicated with dexamethasone at 4 mg/m2 per dose (maximum, 10 mg) the day before the lorvotuzumab mertansine infusion and again approximately 1 hour before the lorvotuzumab mertansine infusion. Acetaminophen and/or diphenhydramine premedication was allowed 30 to 60 minutes before the infusion. Lorvotuzumab mertansine was administered at a rate starting at 0.02 mg/kg/min (maximum, 1 mg/min) for 15 minutes; if it was tolerated, the rate was increased to 0.06 mg/kg/min (maximum, 3 mg/min) to complete the infusion. If the patient tolerated the first infusion, all subsequent infusions were delivered at the 0.06 mg/kg/min rate (maximum, 3 mg/min). Patients experiencing dose-limiting toxicities (DLTs) in the preceding cycle of therapy had their dose modified to 90 mg/m2. Patients were allowed to receive therapy for up to 17 cycles (approximating 12 months) absent disease progression or unacceptable toxicity. Physical examinations, vital sign and performance status assessments, echocardiography, and laboratory studies were performed at the baseline. Thyroid-stimulating hormone levels were obtained at the baseline and at the end of cycle 1. Before subsequent cycles, patients underwent physical examinations and routine laboratory studies. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4. Tumor responses were evaluated with RECIST, version 1.1.17 The best response by RECIST was defined as any RECIST objective response within the first 6 cycles. Patients with neuroblastoma and MIBG-avid disease underwent a central radiological review of curie scores; responses for evaluable MIBG-avid, bone scan?positive or bone marrow disease were assessed according to previously published criteria.18,19 Radiographic disease evaluations were performed after every other cycle until 6 months and then every 3 months. A hematological DLT was defined as grade 4 neutropenia for more than 7 days, grade 3 thrombocytopenia in conjunction with grade 3 bleeding, a platelet count lower than 20,000/?L on 2 separate days, the need for a platelet transfusion on 2 separate days within a 7-day period, or any grade 5 hematological toxicity. Nonhematological DLTs included any grade 3 or higher nonhematological toxicity attributable to lorvotuzumab mertansine with the specific exclusion of grade 3 nausea and vomiting; grade 3 alanine aminotransferase/aspartate aminotransferase elevations that returned to grade 1 or lower or the baseline before the time for the next treatment cycle; grade 3 fever or infection; grade 3 hypophosphatemia, hypokalemia, hypocalcemia, and/or hypomagnesemia responsive to oral supplementation; and grade 3 peripheral neuropathy for 7 days or fewer. DLTs also included any toxicity that caused a delay of 14 days or longer between treatment cycles. PK sampling was required for the first 9 patients enrolled and was optional for patients enrolled subsequently. Peripheral blood samples were collected to determine lorvotuzumab mertansine, total antibody (which measured the concentration of both free HuN901 antibody and conjugated antibody [serum]), and free DM1 (plasma). Concentrations of lorvotuzumab mertansine and total antibody were measured with validated enzyme-linked immunoabsorbent assays. Free DM1 was measured with a validated liquid chromatography?tandem mass spectrometry assay. Blood samples were drawn at the following time points on day 1: before treatment; at the end of the infusion; and 2, 6, 24, and 72 to 120 hours after the end of the infusion. They were also drawn on day 8 before treatment. PK parameters were calculated with standard noncompartmental analysis (Phoenix WinNonlin 6.4; Pharsight Corporation, Mountain View, California).18,19 Tumor CD56 expression was assessed by standard immunohistochemistry with a CD56 antibody, clone 123C3 (Ventana), via a fully automated immunohistochemical staining technique performed with a Ventana Benchmark Ultra staining system.20 Positive staining was interpreted qualitatively as the presence of coarse granular staining of the cell membrane in a circumferential pattern and was scored from 0 to 3+ according to the percentage of positive cells: 0 for 0% to 10% positive cells, 1+ for >10% to 25% positive cells, 2+ for >25% to 50% positive cells, and 3+ for >50% positive cells. A previously identified CD56-positive blastemal Wilms tumor and a patient's tumor sample not treated with the CD56 antibody served as positive and negative controls, respectively. Peripheral blood samples collected on days 1 and 8 (or 11) of cycle 1 before or within 12 hours of starting lorvotuzumab mertansine administration were analyzed for CD56-positive cells with a Miltenyi MACSQuant 10 flow cytometer (Miltenyi Biotec) and a lyse/no-wash staining technique with anti-CD56 allophycocyanin and anti-CD45 fluorescein isothiocyanate antibodies (BD Biosciences). The addition of CD45, a pan-leukocyte marker, allowed for the separation of debris and red blood cells from leukocytes. After blood was incubated with the antibodies and lysed with FACSLyse red blood cell lysis solution, the samples were analyzed on the MACSQuant flow cytometer with a program that yielded both the percentage and absolute number of CD56-positive cells. A single-stage design with up to 16 evaluable patients in each disease cohort was used, with success defined as 4 or more documented responses (partial or complete responses) confirmed by central review within the first 6 treatment cycles in a given cohort. The primary cohorts were defined in terms of Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Once accrual to the primary cohorts was completed, accrual to the other cohorts was suspended unless there was sufficient evidence of responses to continue accrual. The study was designed to compare a null of 15% response rate (RR) to an alternative of 40% RR at a significance level of.079 with 83.3% power. Interim monitoring for excess grade 3 peripheral neuropathy was performed with a Bayesian rule using a ? prior with the parameters ??=?0.6 and ??=?1.2. A posterior probability of at least 80% that the probability of grade 3 peripheral neuropathy was greater than 1 in 3 would have led to a suspension of accrual. Paired peripheral blood samples from day 1 (before therapy) and either day 8 or 11 (after therapy) for the measurement of CD56-positive leukocyte counts were compared with a paired t test on log-transformed counts. The remaining analyses were descriptive. Data current to June 30, 2017, were used for analysis. Novel therapeutic strategies are necessary to increase cure rates for children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, or other CD56-expressing tumors such as pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma. Such cancers nearly uniformly express tumor cell surface CD56 or neural cell adhesion molecule (NCAM).1-15 Antibody-drug conjugate (ADC) therapies that target cytotoxic moieties such as potent antimicrotubule poisons directly against specific tumor cell receptors have been developed. Lorvotuzumab mertansine (IMGN901) is an ADC that links a potent antimitotic (DM1) via a disulfide linker to CD56-targeting antibodies (lorvotuzumab).16 Preclinical data have demonstrated in vivo effects of lorvotuzumab mertansine against Wilms tumor, rhabdomyosarcoma, and neuroblastoma.1,2 We conducted a phase 2 study of lorvotuzumab mertansine administered at the adult recommended phase 2 dose on days 1 and 8 of a 21-day cycle to pediatric and young adult patients with Wilms tumor, rhabdomyosarcoma, neuroblastoma, or other CD56-expressing tumors such as pleuropulmonary blastoma, MPNST, and synovial sarcoma. Data on pharmacokinetics (PK) and pharmacodynamics, including quantitation of the peripheral blood CD56+ cell burden and tumor CD56 expression, were measured.

Funding Information:
This study was supported by an Operations Center Grant from the National Clinical Trials Network (U10CA180886), a Statistics and Data Center Grant from the National Clinical Trials Network (U10CA180899), and the St. Baldrick's Foundation (P30 CA015083). The pharmacokinetic analyses were supported by a grant from the National Cancer Institute (P30 CA015083).

Publisher Copyright:
© 2020 American Cancer Society

Keywords

  • CD56
  • antibody-drug conjugate
  • lorvotuzumab
  • neural cell adhesion molecule (NCAM)

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